Darovasertib Delivers Promising Antitumor Activity in Uveal Melanoma

Neoadjuvant darovasertib elicited strong antitumor activity, reduced simulated radiation doses, and lowered the risk of blindness in patients with uveal melanoma, according to initial findings from IDEAYA Biosciences, developer of the PKC inhibitor.¹

Among 21 patients evaluable for efficacy, 76% (16 patients) reached a response, which the study defined as at least a 20% ocular tumor reduction by product of diameters. Eighty-six percent of patients had at least some reduction in simulated radiation dose to a significant visual structure, with nearly half (48%) of patients experiencing a 20% or higher reduction. The latter is significant as prior research has shown a correlation between a reduced radiation dose of at least 20% and improved visual outcomes.

The efficacy results also showed that darovasertib was associated with at least some visual improvement in 65% of patients. Using a vision tool, the researchers determined that darovasertib was associated with “any reduction” in risk of developing legal blindness (20/200 vision) in 67% of patients, with 38% having a 20% or higher risk reduction.

Darovasertib was observed to be well-tolerated overall among the 39 patients in the safety population. The majority of treatment-related adverse events (TRAEs) were grade 1/2 and manageable. Four (10%) patients experienced TRAEs that were grade 3 or worse. The most frequently occurring TRAEs were diarrhea, nausea, fatigue, maculopapular rash, hypotension, and vomiting. TRAEs resulted in treatment discontinuation for 4 patients: 2 with hepatic transaminase increase; 1 with nausea, vomiting, and fatigue; and 1 with hypotension, bradycardia, and decreased level of consciousness.

"The data presented in this study represent a potential breakthrough advance for [patients] with primary uveal melanoma where there currently is no neoadjuvant therapy available that can shrink tumors in this setting," Arun D. Singh, MD, director of the Department of Ophthalmic Oncology at the Cleveland Clinic Cole Eye Institute in Ohio, stated in a news release.

"We are delighted to see the progress we are making with darovasertib as a single agent in [patients] with midsized tumors requiring plaque brachytherapy," added Darrin Beaupre, MD, PhD, chief medical officer of IDEAYA Biosciences. "Darovasertib is generally well-tolerated and showing initial evidence of shrinking tumors effectively, and the results imply that the associated radiation reduction observed will likely lead to improvements in vision not only during therapy but post-plaque brachytherapy."

OptimUM-09 and OptimUM-10 Trials of Darovasertib in Uveal Melanoma

Overall, the ongoing multicenter, open-label phase 2 OptimUM-09 trial (NCT05907954) is enrolling patients with primary uveal melanoma requiring enucleation or plaque brachytherapy.² Patients need to have an ECOG performance status of 0 or 1, be able to receive oral treatment administration, and have no other major underlying ocular disease. Patients are not eligible for enrollment if they have previously received a PKC inhibitor or if they have 1 or more other primary cancers.

Building on this trial, the open-label, multicenter, randomized phase 3 OptimUM-10 trial (NCT07015190) is exploring neoadjuvant darovasertib in patients with primary nonmetastatic uveal melanoma requiring either plaque brachytherapy or enucleation.³ In cohort 1 of the trial, patients will be randomly assigned to immediate plaque brachytherapy or neoadjuvant darovasertib followed by plaque brachytherapy. Cohort 2 is randomly assigning patients to neoadjuvant darovasertib followed by definitive primary local therapy (plaque brachytherapy, proton beam radiation, or enucleation) or the control arm of immediate enucleation.

Darovasertib previously received breakthrough therapy⁴ and orphan drug designations⁵ from the FDA.

REFERENCES

1. IDEAYA Biosciences Announces Positive Interim Phase 2 Data for Darovasertib in the Neoadjuvant Setting of Primary Uveal Melanoma. News release. IDEAYA Biosciences, Inc. September 8, 2025. Accessed September 11, 2025. https://tinyurl.com/5az3t43n

2. (Neo)Adjuvant IDE196 (Darovasertib) in Patients With Localized Ocular Melanoma. Updated August 3, 2025. Accessed September 11, 2025. https://clinicaltrials.gov/study/NCT05907954

3. Neoadjuvant Darovasertib in Primary Uveal Melanoma. NCT07015190. Updated June 25, 2025. Accessed September 11, 2025. https://clinicaltrials.gov/study/NCT07015190

4. IDEAYA Biosciences receives US FDA breakthrough therapy designation for darovasertib monotherapy in neoadjuvant uveal melanoma. News release. IDEAYA Biosciences, Inc. March 31, 2025. Accessed September 11, 2025. https://tinyurl.com/hfvdvcmr

5. DEAYA Biosciences receives orphan drug designation for darovasertib, a PKC inhibitor, for the treatment of uveal melanoma. News release. IDEAYA Biosciences. May 2, 2022. Accessed September 11, 2025. https://bit.ly/3kzf33A